Systematic Review of Platelet-Rich Plasma in Medical and Surgical Specialties: Quality, Evaluation, Evidence, and Enforcement

Background: Platelet-rich plasma (PRP) is widely used in various medical and surgical specialties for its regenerative properties, including aesthetics (facial rejuvenation, hair restoration, and skin tightening) and orthopedics (treatment of tendinitis and osteoarthritis). However, the inconsistent literature on PRP’s efficacy and safety leads to critical knowledge gaps. This systematic review evaluates quality control measures in PRP preparation and application and explores the regulatory environment governing its clinical use. Methods: Following PRISMA guidelines, a comprehensive search was conducted across multiple databases, including PubMed, EMBASE, and Web of Science, for studies published from January 2020 to April 2024. The review included randomized controlled trials (RCTs) involving human participants undergoing PRP treatment for aesthetic or regenerative purposes. Key parameters such as the PRP preparation methods, platelet concentration, and quality control measures were analyzed. The study protocol was registered with PROSPERO (ID: CRD42024557669). Results: Out of 75 RCTs involving 5726 patients, the review identified significant variability in PRP preparation methods and application techniques, including differences in centrifugation protocols and platelet concentration levels. A new evidence-based scoring system, the William–Eqram Scoring System for PRP Quality Reporting (WESS-PQR), was proposed to address these inconsistencies. Correlation analysis revealed a strong positive correlation (r = 0.79) between proper temperature control during preparation and PRP efficacy. Initial platelet count assessment showed a moderate positive correlation (r = 0.57) with efficacy. Conclusions: Standardized PRP preparation protocols and robust regulatory frameworks are urgently needed to ensure the safety and efficacy of PRP treatments. The proposed WESS-PQR scoring system can serve as a valuable tool for clinicians and researchers, promoting consistency and reliability in PRP applications.

Moreover, the lack of uniform reporting standards has led to difficulties in comparing and synthesizing data from different studies.Despite the promising potential of PRP, the heterogeneity in existing research calls for a concerted effort to establish clear guidelines and reporting standards to enhance the comparability of future studies [105][106][107][108][109][110][111].
There is wide variability in PRP preparation and application methods, including differences in centrifugation techniques, platelet concentration, and the presence of leukocytes.These variations can impact treatment outcomes, yet, to date, no universally accepted standard for PRP preparation has been employed [7,19,32,43,61,67,95,[112][113][114][115][116][117].Commercial PRP separation systems exhibit significant variability, making it essential to understand their unique advantages to effectively extend their clinical application across a broad range of conditions [32,43,118,119].More recently, automation of the PRP production has been developed and promoted to standardize production (e.g., Arthrex Angel™ system) [7,118].
Randomized controlled trials (RCTs) on PRP treatments follow strict protocols to assess efficacy and safety, ensuring standardized procedures and controlled environments [11,21,29,90,101,102].However, the initial scoping review identified significant variability in preparation and application that can significantly impact outcomes.Therefore, it is prudent to explore the quality control measures followed in these studies, including the standardization of PRP preparation methods, consistency of platelet concentrations, and adherence to procedural protocols.
Quality control in PRP preparation and application is another critical area often overlooked.Inconsistent preparation methods and a lack of standardized protocols can lead to unpredictable results and potential safety issues.Evaluating the current quality control measures and identifying best practices is highly desired for ensuring the reliability and effectiveness of PRP treatments [120].
Additionally, the regulatory landscape for PRP therapies is fragmented and varies widely across different regions.This lack of uniform regulation can affect the approval, commercialization, and clinical application of PRP [113,117].A comprehensive review of the regulatory environment is required to identify gaps, propose improvements, and the implementation of quality control checks to ensure the safe and effective use of PRP.
The primary aim of this systematic review is to assess the quality control measures in the preparation and application of PRP.This review will examine the standardization efforts in PRP preparation and propose an evidence-based scoring system for PRP Quality Reporting.The secondary objective is to explore the regulatory environment governing the use of PRP in clinical practice.This review will analyze the current regulatory standards, identify gaps and challenges in regulation, and propose recommendations for improving regulatory oversight to include quality control.

Method
This systematic review with meta-analyses was undertaken following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [121].The review undertaken utilized the format in the Cochrane Handbook for Systematic Reviews of Interventions [122].A concise description of the study protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) (https://www.crd.york.ac.uk/prospero/, record ID: CRD42024557669).

Information Source and Search Strategy
The initial search was performed in February 2024 and updated in April 2024.The databases PubMed/MEDLINE (United States National Library of Medicine, Bethesda, MD, USA), EMBASE (Elsevier, Amsterdam, the Netherlands), Chinese Biomedical Literature Database (CBM), Web of Science (Clarivate, Ukraine), China Network Knowledge Information (CNKI), Chinese Science Journal Database (VIP), and Wanfang Database were searched to identify relevant studies.Grey literature was searched for in the System for Information on Grey Literature in Europe OpenGrey (www.opengrey.eu).All the databases were searched from January 2020 to the present (April 2024).

Study Selection Criteria
Studies were included if they met the eligibility criteria described using the PICOS framework.For the patient population (P), studies involving human participants undergoing PRP treatment for aesthetic or regenerative purposes were selected.Regarding intervention (I), PRP had to be the primary intervention, including various preparation methods and application techniques.In terms of control (C), comparisons to placebo, no treatment, or other standard treatments such as hyaluronic acid fillers or corticosteroids were considered.
The outcomes (O) of interest included quality control measures focused on the standardization of PRP preparation methods, consistency of platelet concentration, and adherence to procedural protocols in the randomized controlled trials.
The study design (S) strictly considered randomized controlled trials published in English.Studies exclusively focused on a specific subset of applications or procedures without broader relevance to the review's scope were excluded.Studies that did not follow the CONSORT guideline or did not provide information in line with the CONSORT checklist were also excluded.
Two authors, ER and WW, independently screened the titles and abstracts of identified studies and removed duplicates.The studies were then exported to the EndNote Reference Library software version 20.0.1 (Clarivate Analytics, Philadelphia, PA, USA) for further management.Next, the articles were thoroughly evaluated to determine whether they met the predefined inclusion criteria.Full texts of potentially useful articles were reviewed in their entirety.Any discrepancies and disagreements were addressed and resolved by the third author, PR.

Outcome of Interest and Outcome Measure
The main outcome of interest was to explore the efficacy reporting of the RCTs in different medical and surgical indications and their correlation to the quality reporting in, I.

Laboratory Tests
Pre-treatment laboratory tests, including a platelet count, to ensure the patient has an adequate platelet level for effective PRP preparation.

II. Standardization of PRP Preparation Methods
Assessing whether studies followed consistent protocols for PRP preparation, including centrifugation protocols [4], final platelet concentration, platelet activation methods, and growth factor concentration reporting.III.Temperature control during preparation, and adherence to aseptic techniques

Data Extraction
For each identified study, relevant data were extracted using a standardized data extraction form.This form captured essential details, including the study characteristics, participant demographics (participant number and condition treated), specifics of the PRP intervention (preparation method and platelet concentration), and efficacy reporting.Extracted data were organized and managed using EndNote and Microsoft Excel or Google Sheets for data organization and preliminary analyses.

Quality Assessment of Studies
The risk of bias in each included study was independently evaluated by two authors (ER and WW) employing the Cochrane risk-of-bias tool for randomized trials (RoB 2).Any discrepancies were resolved by a third author (PR).RoB 2 is designed to address specific aspects of trial design, conduct, and reporting, structured into five domains: bias arising from the randomization process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in the measurement of the outcome, and bias in the selection of the reported result.Each domain contains a set of signaling questions that authors must objectively judge based on the content of the studies.Once these questions are answered, a risk-of-bias judgment is made, categorizing each domain into one of three levels: low risk of bias, some concerns, or high risk of bias.

Proposed Scoring System for the PRP Quality Reporting
We propose the William-Eqram Scoring System for PRP Quality Reporting (WESS-PQR) to address the significant inconsistencies and lack of standardization in PRP preparation and reporting across clinical studies.This comprehensive scoring system evaluates seven critical criteria: initial platelet count assessment, centrifugation protocol, final platelet concentration, platelet activation method, growth factor concentration reporting, temperature control during preparation, and adherence to aseptic techniques.Each criterion is scored on a scale from 0 to 5, with higher scores indicating better adherence to quality standards.The total score ranges from 0 to 35 points, categorized as follows:

Statistical Analysis
Due to the high heterogeneity and variability of the data identified in our scoping review, performing a meta-analysis was not feasible.The studies varied significantly in terms of PRP preparation methods, application techniques, and outcome measures, leading to substantial differences in results that could not be reliably combined.
However, we conducted a correlation analysis to investigate the relationship between PRP Quality Reporting and its efficacy.Specifically, we examined how well-reported quality control measures in PRP preparation (such as initial platelet count, centrifugation protocols, final platelet concentration, and growth factor concentration) correlated with reported efficacy outcomes in the included studies.
All quality reporting metrics were expressed in percentages to standardize the data and facilitate comparison across studies.To visualize the results of this correlation analysis, we generated a heat map.This heat map highlights the strength and direction of correlations between various quality reporting criteria and efficacy outcomes, providing a clear visual representation of the relationships observed.The heat map was created using Python's seaborn library (Waskom, 2021), ensuring that the analysis was both rigorous and reproducible [123].
To ensure the reliability and applicability of the WESS-PQR, we conducted a rigorous validation process.The validation involved several steps: Selection of Studies for Validation: A subset of 20 studies was randomly selected from the included studies to represent a range of PRP preparation and reporting quality; 2.
Independent Scoring: Three independent reviewers, blinded to each other's scores, assessed the selected studies using the WESS-PQR criteria.Each reviewer assigned scores for the seven criteria based on the information provided in the studies; 3.
Inter-Rater Reliability: The consistency of the scores among the three reviewers was evaluated using Cohen's kappa coefficient (κ).A κ value above 0.75 indicates excellent agreement, between 0.60 and 0.75 indicates good agreement, and below 0.60 indicates fair to poor agreement; 4.
Statistical Analysis: The average scores for each criterion and the total scores were calculated.The variability in scores was analyzed using standard deviation (SD) and coefficient of variation (CV).

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There was no patient or public involvement in the design or reviewing process.

Deviation from the Protocol
There was no deviation from the protocol.

Study Selection Process
In the initial search, 585 and 34 records were retrieved from electronic databases and clinical trial registers, respectively.Additionally, 12 records were identified through citation searching.After removing 84 records using the automatic tool and manual deduplication, 547 records were examined with titles, abstracts, and interventions.Subsequently, 91 records from databases, 10 records from registers, and 12 from the citation searching underwent full-text review.Finally, 75 studies were eligible for data extraction and quantitative analysis (Figure 1).citation searching underwent full-text review.Finally, 75 studies were eligible for data extraction and quantitative analysis (Figure 1).

Characteristics of the Included Studies
The systematic review included a total of 75 randomized controlled trials (RCTs) involving 5726 participants, covering a diverse range of medical conditions across various subspecialties (Table 2).

Characteristics of the Included Studies
The systematic review included a total of 75 randomized controlled trials (RCTs) involving 5726 participants, covering a diverse range of medical conditions across various subspecialties (Table 2).

Ocular Conditions
Two RCTs examined the use of PRP in treating dry eye disease (2) [95,130], assessing its impact on tear production and overall eye health.Another study focused on macular holes (1) [143], exploring PRP's potential in promoting retinal healing and improving visual outcomes.

Initial Platelet Count Assessment
Out of the 75 studies, 35 (46.6%) assessed the initial platelet count before PRP preparation.This assessment is vital to ensure that the baseline platelet levels are adequate for achieving a therapeutic concentration after centrifugation.The remaining 40 studies did not report any initial platelet count assessment (53.4%).

Final Platelet Concentration
The final platelet concentration in PRP was reported in 24 out of the 75 studies (32%).These studies generally aimed for a platelet concentration of 3 to 7 times the baseline.For instance, Ye et al. (2024) achieved a 3× to 6× baseline platelet concentration [64] and Efendieva et al. (2023) achieved a 4× baseline concentration [126].However, most studies failed to report the final platelet concentration (68%).

Centrifugation Protocols
Centrifugation is a pivotal step in PRP preparation, influencing the concentration and quality of the final PRP product.The reviewed studies demonstrated a wide range of centrifugation protocols, categorized into single-spin and double-spin methods; 27 studies utilized a single-spin protocol (36%), whilst 31 studies employed a double-spin protocol (41.3%) and 17 did not report anything (22.7%).
Only five studies explicitly reported the RCF used in their centrifugation protocols (6.7%), highlighting a significant gap in standardized reporting with seventy studies failing to report RCF (93.3%).The minimum RPM reported was 500 rpm by Huang et al. (2022) for a single spin lasting 8 min [46], while the maximum RPM was 3800 rpm reported by Navani et al. (2024) with the first spin lasting 1.5 min and the second spin lasting 5 min [99].The shortest spin duration was 3 min (Kang et al., 2023) [95] and the longest was 30 min (Metheetrairut, 2022) [130].

Platelet Activation Methods
Only 14 out of the 75 studies reported using platelet activation methods (18.7%), such as calcium chloride or thrombin.Conversely, 81.3% did not report any activation method, which can impede growth factor release and the overall therapeutic outcomes.

Growth Factor Concentration Reporting
Growth factor concentration, a critical component of PRP's therapeutic potential, was reported in only 5 studies (6.7%) and 70 studies failed to report growth factor concentrations (93.3%).This lack of reporting limits the ability to correlate clinical outcomes with specific growth factor levels and hinders the understanding of PRP's mechanism of action.2022) [31] highlighted the importance of maintaining consistent temperatures to preserve the quality of PRP.

Adherence to Aseptic Techniques
Adherence to aseptic techniques was reported in 65 studies (86.7%), emphasizing the importance of sterility in PRP preparation and administration to prevent infections and ensure patient safety.Conversely, 10 studies (13.3%) did not report aseptic technique adherence.Studies consistently following aseptic protocols are likely to produce more reliable and reproducible outcomes.

Quality Assessment of the Included Studies
In the domain of bias arising from the randomization process, 74% of the studies were assessed as having a low risk, reflecting the use of rigorous and clearly reported randomization methods.However, 19% had some concerns due to insufficient detail on randomization and 7% were rated as high risk due to inadequate or poorly described processes.
For bias due to deviations from the intended intervention, 70% of the studies were judged to have a low risk, indicating close adherence to intervention protocols.Conversely, 23% had some concerns due to minor deviations or incomplete reporting and 7% were assessed as high risk because of significant deviations impacting study outcomes.
In assessing bias due to missing outcome data, 67% of the studies had a low risk, demonstrating adequate management and reporting.However, 29% had some concerns due to incomplete handling of missing data and 4% were rated as high risk due to substantial unaddressed missing data.
Regarding bias in the measurement of outcomes, 68% of the studies were at low risk, ensuring accurate and consistent measurement techniques.Meanwhile, 21% had some concerns due to inconsistencies or incomplete reporting and 11% were assessed as high risk due to significant issues in outcome measurement.
In the domain of bias in the selection of reported results, 73% of the studies were judged to have a low risk, indicating comprehensive and unbiased reporting.However, 20% had some concerns due to potential selective reporting and 7% were rated as high risk due to clear evidence of selective reporting.
Overall, 65% of the included studies were judged to have a low risk of bias across most domains, providing reasonable confidence in their findings.In contrast, 25% had some concerns, primarily due to incomplete or unclear reporting on randomization and intervention protocols, and 10% were assessed as high risk, largely due to significant methodological flaws such as inadequate randomization, missing outcome data, and selective reporting (Table 3, Figures 2 and 3).        4. The assessment of the included studies using WESS-PQR is presented in Figure 4.   4. The assessment of the included studies using WESS-PQR is presented in Figure 4.

Correlation Analysis
The heatmap suggests a strong positive correlation between quality control measures (such as initial platelet count, centrifugation protocol, final platelet concentration, platelet activation method, growth factor concentration reporting, temperature control during preparation, and adherence to aseptic techniques) and PRP efficacy.This indicates that meticulous quality control significantly impacts PRP treatment outcomes.
For example, initial platelet count assessment shows a moderate positive correlation (0.57) with efficacy, suggesting that higher initial platelet counts are associated with improved PRP efficacy.Final platelet concentration demonstrates a strong positive correlation (0.67) with efficacy, suggesting that achieving higher final platelet concentrations is crucial for effective PRP treatments.Temperature control during preparation shows a strong positive correlation (0.79) with efficacy, indicating that maintaining proper temperature control during preparation is vital for PRP efficacy.
While the overall regression model has a p-value (Prob > F-statistic) of 0.356, indicating it is not statistically significant, the individual correlations remain strong (Figure 5).concentrations is crucial for effective PRP treatments.Temperature control during preparation shows a strong positive correlation (0.79) with efficacy, indicating that maintaining proper temperature control during preparation is vital for PRP efficacy.
While the overall regression model has a p-value (Prob > F-statistic) of 0.356, indicating it is not statistically significant, the individual correlations remain strong (Figure 5).

Discussion
The use of PRP across multiple medical disciplines has increased rapidly over the past 20 years [146].However, our study is the largest systematic review of the RCTs across multiple specialties, highlighting the lack of scientific rigor and understanding, i.e., basic and fundamental measurements are not recorded.The studies have shown that over 50% of the studies failed to report baseline platelet counts prior to PRP processing.This is a significant failure due to the wide range of values for healthy platelet counts being 100,000 platelets/µL to 450,000 platelets/µL [2].Furthermore, failure to report post-production platelet counts was identified in 68% of the included studies in this study.The failure to report pre-and post-production platelet numbers prevents the study from reporting the concentration values of the administered PRP.The absence of this crucial data raises significant concerns about the concentration of PRP administered and its potential impact on outcomes and efficacy.This information should be considered the minimum requirement for quality control.The lack of such data highlights a broader issue-the

Discussion
The use of PRP across multiple medical disciplines has increased rapidly over the past 20 years [146].However, our study is the largest systematic review of the RCTs across multiple specialties, highlighting the lack of scientific rigor and understanding, i.e., basic and fundamental measurements are not recorded.The studies have shown that over 50% of the studies failed to report baseline platelet counts prior to PRP processing.This is a significant failure due to the wide range of values for healthy platelet counts being 100,000 platelets/µL to 450,000 platelets/µL [2].Furthermore, failure to report postproduction platelet counts was identified in 68% of the included studies in this study.The failure to report pre-and post-production platelet numbers prevents the study from reporting the concentration values of the administered PRP.The absence of this crucial data raises significant concerns about the concentration of PRP administered and its potential impact on outcomes and efficacy.This information should be considered the minimum requirement for quality control.The lack of such data highlights a broader issue-the insufficient understanding and implementation of quality control systems within healthcare and medicine.
The analysis of the included studies also revealed that the majority reported centrifugation speeds in terms of rpm.However, rpm values alone cannot be standardized due to variations in rotor sizes and designs across different centrifuge models.This inconsistency in reporting centrifugation speeds leads to significant variability in the applied centrifugal forces during PRP preparation, which can impact the reproducibility and comparability of study outcomes.For precise standardization and reproducibility, it is essential to report Relative Centrifugal Force (RCF) instead of rpm [147].
RCF is a measure of the actual force exerted on the blood components during centrifugation and is expressed in units of gravity (g).It provides a consistent and standardized metric and considers both the rpm and the radius of the rotor.
The formula to calculate RCF is where R is the radius of the rotor reported in centimeters.By both calculating and reporting RCF, researchers ensure that the centrifugation process can be accurately replicated across different studies, regardless of the centrifuge model used [147].This standardization is critical because even small variations in the centrifugal force can significantly affect the separation of platelets from other blood components, thereby impacting the quality and efficacy of PRP preparation.The calculation and reporting of RCF should therefore be mandated in PRP research to enhance the reliability, reproducibility, and comparability of the results across different studies and clinical settings [147].
Another crucial aspect of PRP preparation that significantly impacts clinical outcomes is the repeated centrifugation of lysed platelets, inducing the release of their growth factors and other bioactive contents.Studies have shown that lysing the platelets through a second centrifugation step enhances the release of growth factors such as PDGF, TGF-β, and VEGF [148].This elevated release of growth factors correlates with improved clinical outcomes, including faster healing and better tissue regeneration [149].For instance, Amable et al. (2013) demonstrated that repeated centrifugation to lyse platelets significantly increased the concentration of growth factors in PRP, leading to superior clinical results in tissue regeneration applications [112].
Although various PRP kits were utilized across the studies, this does not necessarily guarantee the quality of the PRP produced.The effectiveness and reliability of PRP treatments depend on multiple factors beyond the kit itself, such as the centrifugation protocol, platelet concentration, activation methods, and adherence to standardized procedures.The variability in these factors across different studies suggests that simply using a commercial PRP kit is insufficient to ensure the consistency and quality of the final product.RCF values attributed to centrifugation for standardization were only reported in 6.7% of the included studies and 93.3% failed to report as a scientific standard.Mazzocca et al. (2012) emphasized the importance of quality control in PRP preparation, showing that standardized preparation protocols in RCTs resulted in higher platelet concentrations and better clinical outcomes compared to the non-standardized methods commonly reported in observational studies [115].The findings from Pietrzak and Eppley (2005) highlighted the critical importance of platelet concentration in PRP's therapeutic efficacy [150].Their study reveals a dose-response relationship between platelet concentration and the release of key growth factors such as PDGF and TGF-β.Specifically, they found that PRP with higher platelet counts-up to five times the baseline-resulted in significantly elevated levels of these growth factors, which are essential for wound healing and tissue regeneration [150].
A critical issue identified in this review is the lack of initial assessment of the patient's platelet count before PRP preparation in many studies.According to FDA guidelines (Title 21 CFR Part 640.21) [151], it is essential to assess and monitor the donor's platelet count to ensure that it meets the required thresholds before plateletpheresis begins.Specifically, the donor's platelet count should be at least 150,000 platelets/µL before starting the procedure.Failure to perform this initial assessment can lead to suboptimal platelet concentrations in the PRP, thereby affecting its efficacy.The omission of this critical step in many studies underscores the need for adherence to regulatory guidelines to ensure the quality and effectiveness of PRP treatments.
Quality assurance in PRP therapy is not solely dependent on the technical aspects of preparation and administration.The operator's expertise plays a critical role in ensuring the correct implementation of protocols.Inadequate training and variability in practitioner skills can introduce another layer of inconsistency, affecting the therapeutic outcomes of PRP.Thus, establishing stringent training programs and certification requirements for practitioners is essential to maintain high standards of practice.
Additionally, the lack of standardized quality control measures across different regions and clinical settings can lead to significant disparities in PRP therapy outcomes.This variation calls for the development of universal guidelines that can be adopted globally to harmonize practices.Such guidelines should be based on evidence from robust clinical studies and expert consensus to cover all aspects of PRP therapy, including patient selection, preparation protocols, and post-procedural care (Figure 6).
Additionally, the lack of standardized quality control measures across different regions and clinical settings can lead to significant disparities in PRP therapy outcomes.This variation calls for the development of universal guidelines that can be adopted globally to harmonize practices.Such guidelines should be based on evidence from robust clinical studies and expert consensus to cover all aspects of PRP therapy, including patient selection, preparation protocols, and post-procedural care (Figure 6).[3,152,153].
The International Cellular Medical Society (ICMS) has set forth comprehensive guidelines for PRP usage, stressing standardized preparation techniques, rigorous patient selection, and adherence to procedural protocols [154].However, the adoption and implementation of these guidelines are uneven, leading to significant inconsistencies in The International Cellular Medical Society (ICMS) has set forth comprehensive guidelines for PRP usage, stressing standardized preparation techniques, rigorous patient selection, and adherence to procedural protocols [154].However, the adoption and implementation of these guidelines are uneven, leading to significant inconsistencies in PRP practices.The lack of a unified approach across different regions results in a fragmented regulatory landscape, which ultimately compromises the quality of PRP treatments and may be a major contributing factor to outcome reporting.
The FDA's regulation of PRP under the Code of Federal Regulations Title 21 also mandates stringent criteria for donor eligibility, blood collection, and processing.These regulations emphasize maintaining proper platelet counts and ensuring controlled temperatures during the separation process.While the FDA guidelines are robust, the enforcement and compliance across various clinical settings are inconsistent.This variability can result in suboptimal PRP preparations, directly affecting clinical outcomes and patient safety.The absence of stringent oversight mechanisms exacerbates this issue, leaving gaps that can be exploited by less scrupulous practitioners.
European regulations, governed by directives such as 2002/98/EC and 2005/62/EC, require adherence to Good Manufacturing Practices (GMP) for blood and blood components, including PRP [155].These directives are intended to ensure all steps, from collection to administration and are conducted under strict quality control conditions.However, the enforcement of these standards is inconsistent across different member states.This inconsistency not only leads to variability in PRP quality but also undermines the trust in regulatory frameworks that are supposed to safeguard patient health.The lack of a harmonized enforcement strategy within Europe reveals a significant regulatory shortfall.
In the United Arab Emirates, the Dubai Health Authority (DHA) has established detailed guidelines that mandate licensing for healthcare facilities and certification for practitioners offering PRP treatments [156].These guidelines emphasize using standardized and approved equipment and maintaining aseptic techniques.Despite these comprehensive regulations, the uniformity in enforcement remains questionable.
The regulatory landscape in the United Kingdom, under the Medicines and Healthcare Products Regulatory Agency (MHRA), reveals a significant gap: failure to implement strict guidelines and quality control checks in the manufacture and use of PRP in clinical settings.The absence of specific national guidelines for PRP therapy under the MHRA leads to considerable inconsistencies in PRP application and quality.This regulatory void allows for a wide range of practices, some of which may be suboptimal or even unsafe.The lack of clear standardized guidelines not only affects patient outcomes but also undermines the credibility of PRP therapies.These gaps highlight an urgent need for the MHRA to develop and implement comprehensive guidelines to regulate PRP treatments effectively.Given the paucity of clear regulatory guidelines, it was not possible to ascertain whether the included studies met the geographic-specific regulatory requirements and this again may contribute to the lack of consensus in the use of PRP.
This study boasts several strengths.Firstly, it provides a comprehensive evaluation of PRP preparation and reporting standards across a large number of RCTs, encompassing a wide range of medical and surgical subspecialties.This broad scope allows for a thorough understanding of current practices and highlights areas requiring standardization.Secondly, the development and validation of the WESS-PQR is a significant contribution; this robust scoring system enhances the quality and transparency of PRP research by providing a standardized framework for assessing and reporting PRP preparation methods.
However, the study also has some limitations.Firstly, the variability in study design, PRP preparation protocols, and outcome measures affected the comparability and generalizability of the findings.Secondly, due to the high variability in PRP preparation methods, a meta-analysis was not feasible.We used qualitative synthesis and recommended more standardized study designs for future meta-analyses, which would help in achieving reproducibility and reliability of results.Thirdly, the potential for publication bias cannot be overlooked.Studies with positive or significant results are more likely to be published, while those with negative or null findings may be underrepresented, skewing the overall assessment.Similar trends were observed in the recent systematic reviews [157][158][159][160][161]. Despite these limitations, we used multiple databases and employed independent reviewers to screen and select studies based on predefined criteria.This minimizes selection bias and ensures a comprehensive unbiased inclusion of relevant studies.This methodological rigor supports the reliability of our findings on PRP preparation and reporting quality.
For patients, the findings of this review highlight the importance of receiving PRP treatments from practitioners who adhere to standardized protocols and comply with regulatory guidelines.Patients should be aware of the variability in PRP preparation and seek treatment from certified and well-trained practitioners to ensure the highest quality and efficacy of PRP therapy.Understanding the role of regulatory guidelines can also empower patients to make informed decisions about their treatment options.
For practitioners, this review underscores the critical need for adherence to standardized preparation and application protocols.Practitioners must ensure that they follow established guidelines to maintain the quality and safety of PRP treatments.Additionally, practitioners should stay informed about the latest regulatory requirements and quality control measures to enhance their practice and optimize patient outcomes.The review also highlights the importance of thorough training and certification programs to reduce variability in PRP practices.
Future research should focus on several key areas to address the gaps identified in this review.First, there is a need for large-scale multicentre randomized controlled trials (RCTs) to validate the findings from observational studies and case series.These trials should adhere to standardized PRP preparation and application protocols to provide robust evidence on the efficacy and safety of PRP treatments.Additionally, future studies should include detailed assessments of long-term outcomes to understand the sustained benefits and potential risks associated with PRP therapy.
Future research should explore the molecular mechanisms underlying PRP's therapeutic effects to optimize its use in various clinical applications.Investigating the impact of different preparation techniques on the release of growth factors and cytokines can provide insights into enhancing the efficacy of PRP.
Furthermore, there is a need for the development and validation of universal guidelines for PRP therapy.Comparative studies across different regulatory frameworks can help identify best practices and inform the creation of harmonized standards.Lastly, research should focus on the implementation and enforcement of regulatory guidelines to ensure that they are effectively integrated into clinical practice, thereby improving the consistency and reliability of PRP treatments globally.

Conclusions
The lack of standardized preparation protocols and uneven enforcement of regulatory standards severely compromise the reliability and efficacy of PRP treatments and suboptimal patient outcomes and may be a major factor in a wide variety of outcomes reported in similar studies.To realize the full potential of PRP therapy, there is an urgent need for unified enforceable standards to ensure safety, efficacy, and consistency such as the currently proposed WESS-PQR.Only through such rigorous standardization can we truly harness the regenerative promise of PRP and deliver its benefits to patients worldwide, ensuring the highest standards of care and outcomes.

Figure 1 .
Figure 1.PRISMA flow diagram.The PRISMA checklist has also been included as Supplemental Material-S2 to ensure adherence to reporting guidelines.

Figure 1 .
Figure 1.PRISMA flow diagram.The PRISMA checklist has also been included as Supplemental Material-S2 to ensure adherence to reporting guidelines.

3. 3 . 6 .
Temperature Control during Preparation Temperature control during PRP preparation was mentioned in 19 studies (25.3%), with the remaining 56 studies failing to report temperature control (74.7%).Temperature management is essential to maintain platelet viability and functionality.Studies like those by Efendieva et al. (2023) [126] and Keene et al. (

Figure 3 .
Figure 3. Summary of the Risk of bias.

3. 5 .
Statistical Analysis 3.5.1.Validation Result of the WESS-PQR Cohen's kappa coefficient for the seven criteria ranged from 0.72 to 0.82, indicating good to excellent agreement among the reviewers.The detailed validation statistics are presented in Table

Figure 3 .
Figure 3. Summary of the Risk of bias.

3. 5 .
Statistical Analysis 3.5.1.Validation Result of the WESS-PQR Cohen's kappa coefficient for the seven criteria ranged from 0.72 to 0.82, indicating good to excellent agreement among the reviewers.The detailed validation statistics are presented in Table

Figure 5 .
Figure 5. Correlation matrix heatmap demonstrating a strong and statistically significant relationship between quality control measures and PRP efficacy.

Figure 5 .
Figure 5. Correlation matrix heatmap demonstrating a strong and statistically significant relationship between quality control measures and PRP efficacy.

Table 2 .
Characteristics of the included studies.

Table 2 .
Characteristics of the included studies.

Table 3 .
Risk of bias of the included studies.

Table 4 .
Validation statistics of the William-Eqram Scoring System for PRP Quality Reporting (WESS-PQR).

Table 4 .
Validation statistics of the William-Eqram Scoring System for PRP Quality Reporting (WESS-PQR).